Influenza has been a major public health issue with about 36,000 deaths each year in the United States due to influenza associated disease. The primary approach to minimizing the impact of influenza on the community is to encourage annual immunization. In the past, these immunizations were recommended for targeted populations: elderly individuals, individuals with underlying health conditions, and children under two. While the CDC's recommendations have been expanding over 20 years, for the first time in 2010, influenza immunization was recommended for all individuals without egg allergies. Another recent development is the availability of multiple forms of the influenza vaccine. While a killed vaccine has been utilized since 1945, a live attenuated vaccine was approved by the FDA in 2003. With both the new recommendation for annual immunization for all individuals and the availability of two different preparations of influenza virus, a new question emerges: is there any difference in the ability of elderly to mount a protective immune response after influenza vaccination if they have been immunized through their lives with the attenuated rather than the traditional killed vaccine? Since both the killed and attenuated vaccines are effective in inducing protective immunity in healthy young individuals, there is no basis for choosing one versus the other except convenience. However, if one vaccine is superior in allowing the development of protective immunity to influenza virus in old age, use of that particular form of the vaccine should be encouraged. The purpose of this study is to simulate in mice annual immunizations from childhood through old age and to determine whether or not the protection afforded in old age is superior in those individuals who have received killed vaccine throughout their lives versus those who have received the attenuated vaccine. Mice will receive immunizations beginning at six weeks of age at three month intervals with either killed or live influenza virus. To replicate antigenic drift, each immunization will be performed with H3 variants of influenza A virus. Mice will receive their seventh immunization at 20 months of age and will be challenged with this strain of the influenza virus one month later. The effectiveness of the vaccination will be compared not only between the groups that have received the killed virus and the live virus immunizations, but also to the protection afforded to young mice and aged mice after only one immunization with the seventh virus strain. The effectiveness will be measured by disease symptoms (weight loss and death), antibody production and cell-mediated responses (specific CD8 T cells, including IFN3 and memory phenotype). If differences are observed between the killed and live immunizations, a subsequent R01 grant will determine: 1) the parameters necessary to increase protection (e.g. number of immunizations; timing of immunizations); 2) mechanism of the difference (e.g. altered cell-mediated memory; broadly cross-reactive antibody). These studies have the potential to provide significant information regarding an important public health issue in the light of recent developments.